Sustained release delivery systems for solutes

ABSTRACT

The present invention relates to devices that allow for linear, sustained-release of solutes with adjustable initial-release kinetics. In particular, the present invention relates to devices for delivering substances to the body of an animal. The present invention also relates to methods for delivering solutes in a constant, sustained-release fashion using the devices of the invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to provisional applicationsserial No. 60/190,878, filed Mar. 21, 2000, and No. 60/221,070, filedJul. 27, 2000, both of which are incorporated herein by reference intheir entireties.

FIELD OF THE INVENTION

[0002] The present invention relates to delivery systems that allow forsustained release of one or more solutes. In particular, the presentinvention relates to devices for delivering substances to the body of ananimal or into other environments requiring a constant delivery and tomethods of delivering these substances in a constant, sustained-releasefashion.

BACKGROUND OF THE INVENTION

[0003] Drug delivery classically has been via oral dosage forms thatrelease the drug as they dissolve in the gastrointestinal tract. Thesedelivery systems typically provide for rapid release of the activesubstance, which leads to the presence of maximal concentrations of thedrug in the blood followed by a rapid decrease in concentration as thedrug is metabolized and cleared. At these maximal concentrations, manydrugs are highly toxic. Furthermore, if the concentration decreasesrapidly in the body, then the time during which there is atherapeutically-effective level is short, and therapeutic efficacyrequires administration of multiple doses. In addition, if release of asubstance in the body cannot be controlled, then it may not beeffectively delivered to the site of the body requiring treatment.

[0004] Other solutes also benefit from devices that allow for theirsustained release. For example, dosing of swimming pools with chlorineor hot tubs with bromine as anti-microbial agents currently requiresadding these substances to the water on a fairly regular basis.Furthermore, if the concentration is not controlled and becomes too highupon addition, then the water may not be safe or pleasant for bathersuntil the concentration stabilizes at lower values. Other uses forsustained-release delivery systems include, for example, delivery offood or insecticides to plants, delivery of vaccines, antibiotics,anti-parasitic agents, growth promotants or other drugs to livestock,delivery of sanitizing agents or perfumes to toilets or septic tanks,delivery antibiotics or other drugs to companion animals, delivery ofdyes, bleaches or other substances in the processing of textiles,delivery of algicides to water towers or ponds, delivery of food to fishin aquaria or ponds, and delivery of any substance requiring constantdelivery in an industrial manufacturing process.

[0005] Various sustained release delivery devices have been described,including those in which a solute is contained within an impermeablehousing with one or more openings from which solute egresses bydiffusion. Such devices purport to deliver solute at a constant(zero-order) rate; however, many deviate significantly from zero orderor linear delivery. In addition, such devices often are limited in theamount of total dose deliverable, as well as by fixed parameters thatmake it difficult or impossible to adjust the delivery kinetics. Acommon feature of such prior art devices is that their release kineticsare characterized by an initial burst of solute release prior to aperiod of relatively constant rate of release, and the relativelyconstant rate of release often only crudely approximates zero order. Forseveral reasons, such an initial burst is undesirable, as it temporarilydelivers a dose in excess of the desired, effective dose, thus wastingsolute, and moreover, may deliver an amount of solute which is toxic orotherwise damaging in the particular application. In addition, theinitial release of a large amount of solute reduces the total amount ofsolute subsequently available for prolonged release by the device, thusshortening the duration of relative constant delivery, reducing itseffective life and requiring more frequent replacement.

[0006] The devices and methods of the present invention overcome thedisadvantages of current devices and methods for the delivery of solutesby providing for reliable and adjustable sustained release of solutes inaqueous and non-aqueous environments. In addition to exhibitingadjustable, nearly-constant release rates over suitably prolongedperiods of time, the devices and methods of the invention provide formodulation or suppression of the aforementioned initial burst. Thedevices and methods of the invention may be applied to any of theprior-art devices relying on a fenestration or orifice and a fluid- andsolute-impervious coating, to provide prolonged and near zero-orderrelease.

[0007] Discussion or citation of a reference herein shall not beconstrued as an admission that such reference is prior art to thepresent invention.

SUMMARY OF THE INVENTION

[0008] In a first embodiment, the present invention relates to a devicefor the continuous, linear, sustained release of one or more solutes.The device comprises at least one dispenser, each dispenser comprisingat least one solute reservoir element, the solute reservoir elementdefined by a fluid-impervious and solute-impervious wall and having atleast one orifice therein referred to as a source element, each source,element being in fluid registry with a gradient-forming element, thegradient-forming element having a release orifice. The gradient-formingelement is provided for preventing unwanted initial burst and release ofsolute while promoting controlled, prolonged near-zero-order release.

[0009] The solute reservoir element may have a shape such as but notlimited to a hemisphere, sphere, pyramid, cylinder, tetrahedron,parallelepiped, or polyhedron. A hemisphere- or pyramid-shaped solutereservoir element is preferred. A hemispherical solute reservoir elementis most preferred. Preferably, the ratio of the radius of a hemisphereor portion thereof representing the maximum internal diffusion surfaceof the solute reservoir element, to the radius of the source element, isequal to or greater than about two, and more preferably, the ratiogreater than or equal to about five. Most preferably, the ratio is equalto or greater than about ten.

[0010] The source element is an opening or passageway between the solutereservoir element and the gradient-forming element. It preferably has acircular cross-section but is not so limiting, and may have any shape.

[0011] The gradient-forming element may have a shape such as but notlimited to a hemisphere, sphere, pyramid, cylinder, tetrahedron,parallelepiped, or polyhedron. Preferably, the gradient-modifyingelement is a pyramid, the most preferable pyramid a truncated rightcircular cone (a frustum). More preferred is a right circular cone witha vertex angle of between about 10° and about 135°, and even morepreferred is a vertex angle of about 60° to about 120°. Preferably, therelationship among the dimension of the gradient-forming elementextending from the source element to the release orifice (referred toherein as the height of the gradient-forming element) and the radii ofthe release orifice and the source element are such that the height ofthe gradient-forming element is less than about four times the ratio ofthe square of the radius of the source element to the radius of therelease orifice. More preferably, the height of the gradient-formingelement is less than about two times the aforementioned ratio, and mostpreferably, the height of the gradient-forming element is less than twotimes the aforesaid ratio but greater than one-tenth the aforementionedratio.

[0012] In another preferred embodiment of the present invention, theforegoing device has a cylindrical gradient-forming element, one end ofthe cylinder in fluid registry with the source element, and the otherend providing the release orifice. Preferably, the ratio of the radiusof the hemisphere comprising the solute reservoir element to the radiusof the source element is equal to or greater than about two, morepreferably equal to or greater than five, and most preferably equal toor greater than ten. The height of the cylinder is preferably less thanabout four times its radius, more preferably less than about two timesits radius, and most preferably 0.1 to 2 times its radius. Such devicesare particularly useful for oral delivery of a therapeutic agent,although it is not so limiting.

[0013] In another embodiment, the device of the present invention mayhave a solute reservoir element in the shape of a truncated sphericalcone or a truncated right circular cone. The gradient-forming elementmay have a shape among those described above; preferred is a cylindricalshape. Preferably, the radius of a hemisphere or portion thereofcontained within the cone and representing the maximum internaldiffusion surface is greater than twice the radius of the sourceelement; more preferred is a hemisphere having a radius five to tentimes the radius of the source element; most preferred is a hemispherehaving a radius more than ten times the radius of the source element.The length of the gradient-forming element extending from the openingpreferably is less than four times its radius, more preferably less thantwo times its radius, and most preferably, 0.1 to 2 times its radius.The gradient-forming element may also have a shape of a truncated rightcircular cone, wherein the base of the gradient-forming element is influid registry with the opening of the cone-shaped solute reservoirelement, the dispenser thus having the appearance of a smaller coneextending from the vertex of the larger.

[0014] In yet another embodiment of the invention, modifications ofdispenser with the foregoing characteristics but having the same orsimilar properties are embraced herein. For example, a dispenserparticularly suitable for parenteral use, such as providing at asubcutaneous location, takes the form of a cylindrical-shaped solutereservoir element. A longitudinal sector of the cylinder is absent, thewalls of the cylinder fluid- and solute-impervious. The absentlongitudinal sector-shaped cavity in the cylinder forms theaforementioned gradient-forming element, and its interface exterior tothe cylinder's overall shape forms the release orifice. The sourceelement providing solute from the solute reservoir element to thegradient-forming element is provided in the form of a series of openingsin at least one or both of the two flat faces forming the sector. Aseries of rows of openings parallel to the longitudinal axis of thecylinder are provided, with the rows more closely spaced to the interiorof the sector (i.e., towards the center), and becoming less closelyspaced approaching the exterior surface of the cylinder.

[0015] A similar configuration may also be provided by variously-shapedsolute reservoir elements which are provided with a deep indentation,invagination or cavity contiguous with the exterior of the dispenser,the indentation forming the gradient-forming element. The solutereservoir element and the indentation are fluid- and solute-impervious.As in the previous embodiment, a series of openings between the solutereservoir element and the gradient-forming element provide the necessarysource elements. If a series of rows of openings are provided, they maybe more closely spaced distal to the interface between thegradient-forming element and the exterior of the dispenser, and becomeless-closely spaced towards the exterior. A solute reservoir element ofthe invention may have multiple cavity-type gradient-forming elements,of a combination of both cavity-type gradient-forming elements and thetype of exterior gradient-forming element described above, such as acone or cylindrical extension from the solute reservoir element. Thus,the invention embodies both interior and exterior gradient-formingelements, or combinations thereof in a single dispenser or device. Suchdevices provide the desired release characteristics as described herein,with a zero-order or near zero-order type kinetics and absence of aninitial burst. As noted with the other dispensers, the geometry anddimensions of the devices with interior gradient-forming elements may beeasily tailored to the particular application or needs of the device,including the location, duration, flux, permanence, biodegradability,among other factors.

[0016] Any discussion herein of the general features or aspects of thedevices of the invention are applicable to any or all of the foregoingembodiments.

[0017] In one aspect the solute reservoir element of a device of theinvention is empty. In another embodiment, the solute reservoir elementcontains a porous substrate. In yet another embodiment, the solutereservoir element contains one or more solutes, with or without a poroussubstrate. The release orifice may be coated with a material that issoluble under preselected conditions, such as a preselected pH.

[0018] The one or more solutes contained within a device of theinvention may be, by way of non-limiting example, is a therapeuticagent. Examples of such therapeutic agents include a calcium salt,parathyroid hormone, antihypertensive agents, diuretics, sympatholyticdrugs, vasodilators, calcium channel blockers, analgesics, opioids,non-steroidal anti-inflammatory agents, antihistamines, antidepressants,hypnotics, sedatives, antiepileptic agents, antiarrhythmic agents,antiparasitic agents, antimicrobial agents, chloroquine, anti-Parkinsonagents, antineoplastic agents, contraceptives, hypoglycemics,electrolytes, vitamins, minerals, nutriceuticals, local anesthetics,diagnostic agents, peptide growth factors, hormones, cytokines,stimulants, amphetamine, methylphenidate, antianxiety agents,benzodiazepines, hematopoietic agents, erythropoietin, stem cell factor,interleukins, and mixtures thereof. In a preferred embodiment, the oneor more solutes is an erythropoietin or a chloroquine.

[0019] The one or more solutes may be dissolved in a solvent orpharmaceutically acceptable vehicle, or it may be present in the devicein a dry form. In one embodiment, the one or more solutes is not watersoluble. A device of the invention may also include a solute-modifyingagent.

[0020] In another broad aspect, the invention is directed to a methodfor delivering one or more solutes in a linear, sustained releasefashion, by administering to a desired site of delivery at least onedevices as mentioned above. Such delivery may be orally, sub-lingually,rectally, vaginally, sub-dermally, intramuscularly, ocularly, topically,nasally, aurically, intravenously, or directly into a particularanatomical location.

[0021] In a further broad aspect, the invention is directed to a kitcomprising at least one device as mentioned above.

[0022] Variations in the design of the dispensers of the invention whichprovide the desired release properties are fully embraced herein. Forexample, a dispenser may have a single source element, a singlegradient-forming element, and a single release orifice. Anothervariation comprises a plurality of release orfices. In anotherembodiment, a dispenser may have a plurality of source elements, eachsource element with its own gradient-forming element. In yet anotherembodiment, a gradient-forming element may be associated with severalsource elements, and in a further embodiment, a solute reservoir mayhave a plurality of such gradient-forming elements, each with multiplesource elements. Moreover, a dispenser may have multiplegradient-forming elements, each of which provide a preselected butdifferent release kinetics attributable to the entire dispenser.

[0023] The dispenser may have a shape selected from the group consistingof cone, cylinder, sphere, ellipse, hemisphere, capsule, rod, needle,and sheet. The dispenser or release orifice thereof may be covered orcoated with a removable material to prevent release of the solute untilthe housing had resided in a particular location for a predeterminedtime period, or is subject to particular conditions which cause thematerial to become dislodged and initiate release.

[0024] The device of the invention may be adapted to hold one or more ofthe aforedescribed dispensers. By way of non-limiting examples, thedevice may be singly or multiply fenestrated to permit egress of soluteto the environment after egress from the at least one dispensercontained therein, or the device may be designed to open or degrade torelease the individual dispensers after a certain time period or undercertain conditions. In a further example, the device may be providedwith at least one exterior opening in fluid registry with a releaseorifice in a dispenser contained within. For a device with a pluralityof such exterior openings, each orifice associated with a releaseorifice of a dispenser, each exterior opening is at least threerelease-orifice-radii apart from another, preferably ten radii apart.

[0025] The solute reservoir element may be filled with one or moresolutes in adequate quantity to supply the source element of the device,and the gradient-forming element optionally may be filled with the oneor more solutes.

[0026] In a second broad aspect, the present invention relates to amethod for delivering one or more solutes in a linear, sustained releasefashion, comprising administering to the site of delivery said solute orsolutes in a device comprising at least one dispenser as describedhereinabove, the dispenser containing at least one solute or capable ofbeing filled with at least one solute. Using the device, the one or moresolutes may be delivered into the body of an animal, for example,orally, sub-lingually, rectally, vaginally, sub-dermally,intramuscularly, ocularly, nasally, aurically, intravenously, on thesurface of the skin, or directly into a specific anatomical location.

[0027] In a third aspect, the present invention relates to a kit,comprising a device for the continuous, linear, sustained release of asolute, the device comprising at least one dispenser as describedhereinabove.

[0028] These and other aspects of the present invention will be betterappreciated by reference to the following drawings and DetailedDescription.

BRIEF DESCRIPTION OF THE FIGURES

[0029]FIG. 1 depicts a schematic of the general shape of a non-limitingexample of a dispenser of the invention, the example having ahemispherical solute reservoir element, a circular opening, the sourceelement, in the center of the flat face of the hemisphere, and afrustoconical-shaped gradient-forming element having a release orificefrom which solute is released.

[0030]FIG. 2 shows another schematic of the device of FIG. 1, withcertain surfaces labeled.

[0031]FIG. 3 depicts the time-dependent efflux of chloroquine from aprior art, hemispherical-shaped device with a 1.5 mm fenestration.

[0032]FIG. 4 shows the time-dependent efflux of chloroquine from ahemispherical solute reservoir element with a frustoconicalgradient-forming element with a 1.5 mm release orifice.

[0033]FIG. 5 shows the time-dependent efflux of chloroquine from ahemispherical solute reservoir element with a frustoconicalgradient-forming element with a 3.0 mm release orifice.

[0034]FIG. 6 compares the release from a marketed chloroquinepreparation (ARALEN) to two devices of the present invention.

[0035]FIG. 7 compares in-vivo release of chloroquine from a prior artdevice to one of the present invention.

[0036]FIG. 8 depicts the cumulative release of albumin from a device ofthe invention over 24 hours.

[0037]FIG. 9 shows the results of an in-vivo experiment comparing theresponse to a single dose of subcutaneously-administered erythropoietinto a parenterally-implanted device of the invention containing the sameagent, which was delivered over a three-week period.

[0038]FIG. 10 shows a device of the invention with a hemisphericalsolute reservoir element, a tubular gradient-forming element, with aplurality of release orifices provided around the base of thegradient-forming element.

[0039]FIG. 11 shows a device of the invention having a cube-shapedsolute reservoir element, with the gradient-forming element provided asa tubular cavity extending partway through the solute reservoir element.Source elements are provided as a series of circumferentialfenestrations about the tubular cavity, closely spaced near theinterior-most part of the gradient-forming element and becoming moredistantly spaced approaching the single release orifice at the surfaceof the cube.

[0040]FIG. 12 depicts a device similar to that in FIG. 11, with threegradient-forming elements in a single solute reservoir element.

[0041]FIG. 13 shows a three-dimensional rendition of a preferred deviceof the invention which comprises a single source element and singlegradient-forming element.

[0042]FIG. 14 shows a device of the invention suitable for parenteraladministration, comprising a tubular-shaped solute reservoir element, anabsent longitudinal sector providing the gradient-forming element, and aplurality of rows of openings therebetween being closer together at thecenter of the tubular element and becoming more distantly spaced towardsto exterior, the openings forming the source element.

[0043]FIG. 15 depicts a device of the invention with a hemisphericalsolute reservoir element and a cylindrical gradient-forming element, anda circular release orifice.

[0044]FIG. 16 depicts the general shape of another embodiment of theinvention which comprises a frustoconical-shaped solute reservoirelement and a cylindrical gradient-forming element.

[0045]FIG. 17 depicts a capsule-shaped device comprising ahemispherical-shaped solute reservoir element with a cylindricalgradient-forming element continuous with the outer surface of thedevice.

[0046]FIG. 18 illustrates how multiple dispensers with differing releasekinetics can be incorporated into a single device so as to deliversolute in a manner unobtainable by a single dispenser.

[0047]FIG. 19 compares theoretically the relative flux from afrustoconical device with no gradient-forming element, showing aninitial burst and first-order release, as compared with identicaldevices but with cylindrical gradient-forming elements of 1/3, 1/7, andthe radius of the source element or release orifice. The devices withgradient-forming elements show no initial burst and near zero-orderrelease.

[0048]FIG. 20 illustrates the actual release of chloroquine fromfrustoconical devices constructed according to the theoreticalcalculations generated for FIG. 21. As experimentally verified for a 1:3ratio, a cylindrical gradient-forming element will not only blunt theinitial burst of release, but will also increase the delivery rate forprolonged periods of time compared to a dispenser lacking agradient-forming element.

[0049]FIG. 21 illustrates that a frustoconical solute reservoir elementwith a cylindrical gradient-forming element can be designed to deliverchloroquine in a zero-order manner, in contrast to a frustoconicalsolute reservoir element alone which delivers with an initial burst,followed by a rapid exponential decay.

[0050]FIG. 22 illustrates the cumulative delivery of chloroquine by thedevices depicted in FIG. 21.

[0051]FIG. 23 illustrates a dispenser consisting of a frustoconicalsolute reservoir element and a cylindrical gradient-forming elementdesigned for the sustained release of drug over 1 day when administeredorally.

[0052]FIG. 24 illustrates what changes in geometry are necessary fromthe dispenser illustrated in FIG. 23 to deliver the load of drug in asustained fashion over 2 days.

[0053]FIG. 25 illustrates one design for a parenteral device to deliverprotein at a low, constant rate for about 30 days.

[0054]FIG. 26 shows an intermediate form in the process of themanufacture of a preferred embodiment of the invention.

[0055]FIG. 27 depicts the release kinetics from up to 12chloroquine-containing dispensers grouped together.

DETAILED DESCRIPTION OF THE INVENTION

[0056] The present invention is directed generally to various devicescapable of delivering one or more solutes at a controlled, predeterminedrate, over a prolonged period of time, with zero order or near zeroorder kinetics, without an initial burst. The parameters for a devicewith these desirable features may be determined by the teachings herein.The ability to control the delivery of a solute, by way of non-limitingexample, a pharmacologically-active agent into the circulation of ananimal at a controlled rate of release for an extended period without aninitial burst, offers the advantages of maintainingtherapeutically-effective levels over a prolonged period of time withoutwaste of excess solute, for safe, effective, convenient and economicalprophylaxis or therapy. Pharmaceutical agents with a narrow therapeuticindex, for which an initial high level of release would be unacceptable,is but one example of a benefit of the instant devices over thosepreviously known. Beyond pharmaceutical agents, the devices, methods andkits of the invention may be applied to the predetermined, controlleddelivery of any solute or solutes from the instant devices into anexterior environment. The flexibility of the parameters of the presentdevices provides the ability to design a device with the aforementionedfeatures for particular specifications which prolonged release andabsence of initial burst are desired.

[0057] The invention herein is broadly drawn to a controlled releasedelivery device, and methods for delivering one or more solutes usingthe device, in which solute egresses from the device by diffusion fromone or more openings in an otherwise fluid- and solute-imperviouscontainer. As will be seen below, the various elements which comprisethe dispenser of the invention may be readily tailored to provide theparticular desired release parameters such as duration and solute flux.

[0058] The dispenser of the present invention has at least four elementswhich contribute to its delivery properties. Each of the individualelements will be described in further detail below; the presentdiscussion is directed to the interaction between the elements whichprovides the delivery features of the dispenser heretofore unachievablewithout the combination of these elements.

[0059] The solute reservoir element is provided to contain all or thebulk of the solute desirous of being delivered by the dispenser. Atleast one opening, termed the source element, is provided between thesolute reservoir element and a chamber referred to as a gradient-formingelement. The gradient-forming element has at least one release orifice.The gradient-forming element provides a means for creating a solutegradient extending from the source element towards the release orifice.This gradient is provided such that the desired solute releasecharacteristics of the device are achieved. The gradient-forming elementmay or may not be filled with solute, so as to provide an initial bolusrelease ranging from a maximum level to no bolus release.

[0060] The solute reservoir element of a dispenser of the invention maybe of any three-dimensional shape, such as but not limited to ahemisphere, sphere, pyramid, cylinder, tetrahedron, parallelepiped, orpolyhedron. A hemisphere or a pyramid are preferred. Most preferred is ahemispherical-shaped solute reservoir element or a shape whichefficiently comprises a hemisphere, i.e., a hemispherical shape resideswithin the overall shape of the solute reservoir element. As will benoted below, the dimensions of the solute reservoir element aredescribed by the diameter of the largest hemisphere that can fit withinthe solute reservoir element with the position of the source element atthe center of the diameter.

[0061] If the solute reservoir element is a hemisphere or a shape whichcomprises a hemisphere, the source element is preferably provided at thecenter of the flat face of the hemisphere or its equivalent. Forexample, a cube-shaped solute reservoir element with an opening (sourceelement) at the center of one of the faces comprises a hemisphere havinga radius equal to one-half the length of the sides.

[0062] As will be evident below, the preferred shapes to which thedispensers of the invention subscribe essentially have a hemisphere or aportion of a hemisphere at their core. Zero-order or near zero-orderrelease occurs during the period of release when the enlarging cavity ofegressed solute defines a hemispherical shape. Later release is linear,unlike other devices, which are by an exponential decay. Thus, a shapeof the solute reservoir element which efficiently comprises a hemispherewill provide the least amount of wasted solute which may not be releasedby the desired kinetics, at the end of the working life of the device.However, for the reasons described herein, other reasons may dictate theshape of the device and the waste or lack of desired release profile maynot be important for the particular use or location of the device. Thus,the efficient hemispherical shape of the solute reservoir element ispreferred but not essential.

[0063] The release characteristics of the devices of the invention areprovided for devices with certain preferred and most preferredcharacteristics, although the invention is not so limiting and one ofskill in the art can readily design a device with the proper dimensionsand solute content to provide the desired duration and release kinetics.In a preferred embodiment, the solute reservoir element is a hemisphereor comprises a hemisphere, and the source element is a circular openingcentered on the flat face of the hemisphere, the source element having aradius. The gradient-forming element is a truncated right circular cone,also referred to as a frustum, whose base (the larger end) is in fluidregistry with the source element, the base of the frustum and theopening forming the source element being one and the same and thushaving the same radius. The truncated end of the cone (the vertex of thefrustum) forms the release orifice. In the example of this embodiment,preferably, the ratio of the radius of the hemisphere, or portionthereof representing the maximum internal diffusion surface of thesolute reservoir element, to the radius of the source element, is equalto or greater than about two, and more preferably, the ratio is equal toor greater than about five. Most preferably, the ratio is equal to orgreater than about ten. As noted above, preferably thegradient-modifying element is a pyramid, the most preferable pyramid atruncated right circular cone. More preferred is a right circular conewith a vertex angle of between about 10° and about 135°, and even morepreferred is a vertex angle of about 60° to about 120°. In thisembodiment, preferably, the relationship among the linear dimension ofthe gradient-forming element extending from the source element to therelease orifice (referred to herein as the height of thegradient-forming element), and the radii of the release orifice and thesource element, are such that the height of the gradient-forming elementis less than about four times the ratio of the square of the radius ofthe source element to the radius of the release orifice; morepreferably, less than about two times the ratio, and most preferably,between about 2 times and about 0.1 times the ratio. Based on thedimensions labeled in FIG. 1, the foregoing relationships can beexpressed mathematically as follows. With regard to the relationshipbetween the radius of the hemisphere within the solute reservoirelement, R_(sr), and the radius of the source element R_(se),preferably, ${\frac{R_{sr}}{R_{se}} \geq 2}\quad;$

[0064] ; more preferably, ${\frac{R_{sr}}{R_{se}} \geq 5};$

[0065] ; and most preferably, $\frac{R_{sr}}{R_{se}} \geq 10.$

[0066] . With regard to the relationship between the height of thegradient-forming element, B, and the radius of the source element R_(se)and the radius of the release orifice R_(ro), preferably${B \leq {4\frac{R_{se}^{2}}{R_{ro}}}};$

[0067] more preferably, ${B \leq {2\frac{R_{se}^{2}}{R_{ro}}}};$

[0068] and most preferably,$\frac{R_{se}^{2}}{10R_{ro}} \leq B \leq {2{\frac{R_{se}^{2}}{R_{ro}}.}}$

[0069] . B can be even less than 0.1 the foregoing.

[0070] The three-dimensional shapes of the solute reservoir element aswell as other components of the devices or dispensers referred to hereinmay be described as follows. The term “pyramid” refers generally to apolyhedron with one face a polygon (the base) and all of the other facestriangles or polygons meeting at the vertex (the apex). Thecross-section of a pyramid decreases from the base to vertex, and maydecrease while maintaining the same cross-sectional shape, or the shapemay change shape or orientation from base to tip, such as in a spiralcone. Various types of pyramids include cones, triangular pyramids,square pyramids, pentagonal pyramids, etc., depending on the number ofsides. A cone is a particular type of pyramid in which the base andcross-section are circular. A truncated pyramid results in a shapecalled a frustum. A right circular cone has a flat base; a sphericalcone has a spheroidal base. By way of illustration, a right circularcone with a vertex angle of about 30° has the shape of an empty icecream cone, with the vertex being the “tip” and the base being thereceiving portion for ice cream. The spherical cone as referred toherein may be described as particular three-dimensional cone-likegeometric shape derived from a sphere, extending from the center of thesphere to the surface. A spherical cone has the shape of an ice-creamcone filled with only enough ice cream to provide a domed bulge abovethe rim of the cone, all points on the dome being equidistant from thetip of the cone. Generally, both the right circular cones and sphericalcones may be referred to collectively herein as cones. To provide theopenings, the cones may be truncated, i.e., the vertex (“tip”) of thecone is cut off, preferably but not necessarily at a right angle to thelongitudinal axis of the cone. The resulting shape is referred to as afrustoconical shape. As will be seen below, for the purposes of theinvention, right circular cones and spherical cones may have vertexangles (i.e., the angle that forms the “point” of the cone) greater thanzero and less than 180°. The shapes of the gradient-forming elementswith small vertex angles may resemble needles; those with large vertexangles may approach the shape of a hemisphere. The value hereinrepresented by 0 (the Greek letter theta) is one-half of the vertexangle, as shown in FIG. 1.

[0071] In another preferred embodiment of the invention, a devicesimilar to the example described above is provided, but having acylindrical gradient-forming element. In this instance, the radius ofthe source element and that of the release orifice are the same.Preferably, the radius of the hemisphere or portion thereof representingthe maximum internal diffusion surface is greater than twice the radiusof the gradient-forming element (radius of the source element or therelease orifice); more preferred is a hemisphere having a radius morethan about five times the radius of the cylinder; and most preferred isa hemisphere having a radius more than ten times the radius of thecylinder. In addition, the height of the cylinder (gradient-formingelement) extending from the source element to the opening preferably isless than four times the radius of the cylinder, more preferably lessthan two times the radius, and most preferably, 0.1 to 2 times theradius.

[0072] In another aspect of the invention, a device may comprise asingle solute reservoir element with a plurality of source elements andassociated gradient-forming elements each gradient-forming elementhaving an orifice. Each source element and associated gradient-formingelement is located maximally apart from the others such that theegressing solute about each source element slowly forms anever-enlarging hemispherical cavity, each enlarging cavity maintainingseparation from the others until one or more meet and fuse at some timeafter a prolonged period of zero-order release. For example, acapsule-shaped device may be prepared, comprising a single mass of solidsolute, wherein each of one or more release orifices from which soluteis released from the device is associated with a gradient-formingelement and a source element extending from the single mass of solute.In a further embodiment, the release orifices may be covered or pluggedwith a material that is soluble in the small intestine but not in thestomach. Upon swallowing, the capsule passes through the stomach intact;on exposure to the small intestine, the coating dissolves, and releaseof solute is initiated, without initial burst and with near zero-orderkinetics. Continued passage of the capsule through the digestive tractresults in the desired delivery of the solute from the multiple openingsover a prolonged period of time.

[0073] The term “device” and “dispenser” may be used interchangeably,although it is understood that a device of the invention may compriseone or more similar or dissimilar dispensers.

[0074] The terms “excipient” or “solute-modifying agent” is definedherein as any substance included in the solute reservoir element and/orgradient-modifying element of the device which is not the solute (e.g.,therapeutic agent, perfume, algicide, etc.) and serves to alter thecharacteristics of the solute or of the operation of the device.Examples include compounds which alter the biological activity of thesolute, for example to inactivate the biological activity of the soluteduring residence in the device, to aid in the precipitation of thesolute within the device; to alter the pH to maintain stability; topromote solubility; to reduce or prevent immune recognition of thesolute within the device; to dissuade entry of immune or other cellsinto the orifice; or to modulate the viscosity of the solute. Examplesof such compounds are described hereinbelow. Excipients also extend toporous matrices, sponges, or other materials which are provided with thesolute within the dispenser for the purpose of, for example, stabilizingthe contents from agitation, spillage, etc.

[0075] A device of the invention comprises at least one of theabove-described dispensers. It may be formed as a finished product in ashape to enhance the handling, mounting, delivery, fixation, swallowing,insertion, removal, and other esthetic and/or practical considerationsin employing one or more dispensers for particular intended purposes, aswill be elaborated upon further below. More than one dispenser may becontained within a housing; a plurality of similar or dissimilardispensers, e.g., with different solutes or release characteristics, ofdifferent shapes, may be placed within a single housing.

[0076] In the devices of the present invention, the parts that determinethe flux of solute include (1) a shaped cavity or housing wherein theone or more solutes is present (i.e., the solute reservoir element); (2)a fluid- and solute-impervious wall surrounding the cavity that isfenestrated with at least one opening (the source element); (3) agradient-forming element into which the solute diffuses from the sourceelement; and (4) a release orifice in the gradient-forming element fromwhich solute flows out of the dispenser. The size of the solutereservoir element can range without limit, depending on the physicalsize of the device and can be very small to very large. In oneembodiment, the dispensers consist of a cavity that is filled only withsolute with or without binders or excipients. Acidic, basic, oramphoteric excipients may be included to promote solubility of thesolute within the dispenser or maintaining solubility after release,such as is described in an example below. The stricture of the deviceensures that these modifying components persist with the other solute orsolutes within the device to enable continuous solute delivery.

[0077] In another embodiment, the cavity of the solute reservoir elementis filled with a porous or gel-like substrate that allows a stableconcentration gradient to be established. The porous substrate caninclude, but is not limited to, agar, polyvinyl sponges, microporousbeads, or polymer fibers. The nature of the porous substrate and theparameters of the gradient-forming element will predictably influencethe rate of release of a solute from the device. Without being bound byany theory, the porous substrate effectively decreases the diffusioncoefficient. Addition of a matrix may also provide a means formaintaining the concentration gradient inside the solute reservoirelement in environments with extreme turbulence.

[0078] As mentioned above, the solute reservoir element has ageometrical shape that may be but is not necessarily symmetrical aboutthe axis perpendicular to the plane of the source element. A symmetricalgeometric shape for the dispensers of the invention is preferred as suchshapes have been identified by calculation to allow for the mostefficient prolonged nearly constant or linear delivery of solute. Theimpervious casing surrounding the dispenser or the entire device may benon-biodegradable or biodegradable. Alternately, the entire device orthe release orifice(s) may be coated with a material that regulatesrelease, e.g., a plug which dissolves under certain conditions andrenders the orifice patent. Preferably, the device is made from one ormore non-reactive and biocompatible polymers that include, but are notlimited to, acrylonitrile polymers such asacrylonitrile-butadiene-styrene terpolymer; halogenated polymers orco-polymers such as polytetrafluoroethylene andpolychlorotrifluoroethylene; polyimide; polysulfone; polycarbonate;polyethylene; polypropylene; polyvinylchloride-acrylic co-polymer;dialkyl fumarate; vinylidene chloride and polystyrene, methyl cellulose,polyethylene glycol or combinations thereof. Biodegradable polymers suchas polylactides and polyesters, as well as modified cellulosederivatives such as methylcellulose, may be employed.

[0079] As mentioned above, prior art matrix or reservoir devices relyingon diffusion for delivery have been unsatisfactory for a number ofreasons including initial burst release, significant deviation from zeroorder or linear delivery, significant limitation of total dose deliveredand rigid parameters, all of which make it difficult to adjust thedelivery kinetics, including the duration of delivery. Prior artdiffusion devices utilizing a small opening compared to the enclosedvolume of solute are characterized by potentially quasi-zero orderrelease for times late in the release after the initial burst or dumpingof solute. Adjustment of release parameters is relatively insensitive tochanging the dimensions of the opening, as flow of solute through theopening is directly proportional to its linear dimension.

[0080] An improvement of such devices can be obtained by utilizingdevices of various sizes and shapes surrounded by a membrane impermeableto both the contents and the medium in which it is placed. This membraneis fenestrated at one location (defined by theoretical analysis asoutlined elsewhere) by providing a source element (an opening), and isprovided with a chamber in which the efflux of solute from the sourceelement is modified by the gradient-forming element to provide thedesired release characteristics at the release orifice. This chamber,referred to herein as a gradient-forming element, may be very muchsmaller in size than the solute reservoir element, and may appear onlyas a conical (or another shaped) bump on the solute reservoir element.The gradient-forming element initially may be devoid of solute, or itmay be filled with solute, as the solute reservoir element, prior torelease.

[0081] Prior art, fenestrated devices, whether containing a matrix orfunctioning as a reservoir only, operate in a well-described mannercharacterized by an “amplification” of the internal concentrationgradient to provide a relatively high concentration at the surface ofthe fenestration. As diffusion of solute proceeds out of the device,diffusion fronts of constant concentration are established which takethe form of concentric hemispheres for depths greater than one to twotimes the cross-sectional linear dimension of the fenestration. Thismeans that there is increasing solute diffusion from the depths of thedevice to the surface, such as to tend to maintain the concentration atthe opening at a steady state. If enough solute and the dimensions ofthese devices are optimized, nearly-linear release rates can be obtainedfor varying lengths of time. The initial release of solute from thefenestration occurs generally at a high concentration so that an initialburst of release occurs.

[0082] The present invention provides a method by which fenestrateddevices of any configuration can be modified to provide a release closerto zero order, dampening of the initial burst of release, prolongationof delivery duration, and offer the ability to precisely and easilydesign a device of a required size or shape to deliver at a specificrate. In its most basic form, the gradient-forming element acts as acomponent to add impedance or resistance to the outflow of solute fromthe fenestration (source element). Upon initiation of diffusive release,which might occur, for example, when an orally-administered device ishydrated within the alimentary tract, the initially efflux of soluteoccurs into the empty gradient-forming element at a rate defined by thediffusive resistance of the gradient-forming element and theconcentration of solute at the source element. Movement of solute fromthe interior of the device (solute reservoir element) is contributed byan increasing surface area of diffusion in direct relationship todistance from the entrance of the source element. In this manner, solutewhich leaves the interior of the device is replaced by solute fromdeeper within the device. As the diffusion front proceeds through thegradient-forming element, it reaches the external environment with adelay and initially at a much lower concentration than that of solute atthe source element, i.e., at the fenestration or opening. Aftersufficient time, a steady-state rate of diffusion is established fromthe concentration gradient that has been established from the interiorof the device through the gradient-forming element. This can bemathematically estimated using variations of the equation below.

[0083] The addition of a frustoconical-shaped gradient-forming elementto a hemispheric solute reservoir element can increase and prolong thedelivery rate compared to a hemisphere alone. This modificationaccomplishes this by maintaining the release orifice time-dependentconcentration higher than it would be at an identical orifice in theface of the hemispherical solute reservoir element. The gradient-formingelement prevents a too-rapid exit of solute from the device, whichtranslates into a lower peak delivery rate, but at a higher and moreprolonged quasi-steady state plateau.

[0084] The difference between the quasi-steady state release rates of ahemisphere compared to a frustoconical hemisphere can be seen bycomparison of the relevant equations. The equation describing thisquasi-steady state flux, i, from a hemisphere of radius R_(s) with exitpore of radius R_(B) is given by:$i = \frac{\pi \quad R_{B}R_{s}\quad {DC}_{0}}{\frac{( {R_{B} - R_{s}} )}{2} + \frac{\pi \quad R_{s}}{4}}$

[0085] The following equation describes quasi steady-state flux, i, froma dispenser with a frustoconical adjustable resistance element, such asis shown in FIG. 1. Variables are indicated in FIG. 1. The value of θrepresents one-half of the vertex angle (i.e., the vertex angle is 2θ).$i = \frac{\pi \quad R_{ro}R_{se}{DC}_{0}}{\frac{( {R_{{se}^{-}}R_{sr}} )R_{ro}}{R_{sr}8} + \frac{\pi \quad R_{se}}{4} + \frac{\tan \quad {\theta ( {R_{ro} - R_{se}} )}}{2( {1 - {\cos \quad \theta}} )}}$

[0086] The preferred dimensions of the device are described byexpressing the cross-sectional area in terms of corresponding circleswith equivalent surface areas. As shown in FIG. 2, the source elementhas cross-sectional area A_(se), and the release orifice has across-sectional area represented by A_(ro). Release characteristics fordevices in which the source element and/or release orifice are notcircular can be calculated by determining the equivalent radius of theopening were it to have an equal circular cross-sectional area.Alternate openings may be, by way of non-limiting example, ellipticaland square, and the shape of the gradient-forming elementcorrespondingly shaped.

[0087] In the instance wherein the gradient-forming element is acylinder, such as is shown in FIG. 15, and thus R_(ro) and R_(se) arethe same, the height of the cylinder being B, the steady-state releaseis described by the following formula:$i = \frac{\pi \quad R_{se}^{2}\quad {DC}_{0}}{\frac{( {R_{{se} -}R_{sr}} )R_{se}}{2R_{sr}} + \frac{\pi \quad R_{se}}{4} + B}$

[0088] Such a device with a cylindrical device may be easier tomanufacture, as, for example, the finished dispenser can have the shapeof a hemisphere with the source element and gradient-forming element atthe center of the flat face, in which the thickness of the coating onthe flat surface provides the height of the gradient-forming element.

[0089] In the instance wherein the gradient-forming element iscylindrical, and the solute reservoir element may be hemispherical orcomprises a hemispherical shape with the source element centered on theflat face of the hemisphere, preferably, the radius of the hemisphere orportion thereof representing the maximum internal diffusion surface isequal to or greater than greater than about twice the radius of thegradient-forming element (radius of the source element or the releaseorifice); more preferred is a hemisphere having a radius more than aboutfive times the radius of the cylinder; and most preferred is ahemisphere having a radius equal to or more than ten times the radius ofthe cylinder. In addition, the height of the cylinder (gradient-formingelement) extending from the source element to the opening preferably isless than four times the radius of the cylinder, more preferably lessthan two times the radius, and most preferably, 0.1 to 2 times theradius. The ratio of the radius of the cylinder to the radius of thehemisphere which gives the maximum efflux while still blunting theinitial surge of release is 0.08 to 0.086, or about 1:12. Theseparameters are non-limiting and merely illustrative.

[0090] In another preferred embodiment, the solute reservoir element ofthe dispenser of the invention has the shape of a truncated rightcircular cone or a truncated spherical cone. These shapes are describedabove. The gradient-forming element may have any shape which providesthe desired release characteristics, such as but not limited to either afrustoconical or cylindrical shape. These preferred shapes of thegradient-forming element are as described hereinabove with regard to thehemispherical-shaped solute reservoir element. All other aspects andadditional features of the foregoing dispensers are applicable to thisembodiment as well.

[0091] In this particular embodiment, the more preferred cone-shapedsolute reservoir element has a vertex angle of between about 10° andabout 135°, and even more preferred is a cone with a vertex angle ofabout 60° to about 120°. The cone with a vertex angle of 180° is ahemisphere, and is described previously. The source element ispreferably provided at the vertex of the solute reservoir element, i.e.,where the tip of the cone is truncated. For a device as described with aconical-shaped solute reservoir element and a frustoconical orcylindrical gradient-forming element, the foregoing equations may beused to indicate the solute flux from the release orifice of the device,when the radius of the largest hemispherical solute reservoir containedwithin the cone, and the source element positioned at the vertex of thecone, is used. In addition, the preferred and most preferred embodimentsare similar. By way of non-limiting example, the useful range of deviceparameters of the above-mentioned device with a cylindricalgradient-forming element of the invention are as follows. Rsphere (themaximum radius of the internal diffusion surfaces) is preferably greaterthan twice the radius of the gradient-forming element, more preferably 5to 10 times the radius, and most preferably greater than 10 times theradius. The ratio of the radius of the gradient-forming element to theradius of the sphere which gives the maximum efflux while still bluntingthe initial surge of release is 0.080 to 0.086, or about 1:12. Withregard to the height and radius of the gradient-forming element, thegradient-forming element length preferably may be less than 4 times itsradius, more preferably less than 2 times its radius, and mostpreferably 0.1 to 2 times its radius. These parameters are non-limitingand merely illustrative.

[0092] Thus, by following the teachings herein and the foregoingequations, the skilled artisan may readily construct a device for aparticular application, thus delivering a particular solute or solutesover an extended period of time with zero order or near zero orderkinetics. Any reduced delivery rate that is dictated to provide thedesired release characteristics for a particular size or shape of devicemay be offset by increasing the concentration of the solute (C₀) withinthe solute reservoir element, or by changing the geometry by theteachings conveyed herein.

[0093] In one embodiment, the release orifice of the device is coated(and/or the gradient-forming element filled) with a material that issoluble only under a particular set of conditions. In a preferredembodiment, the release orifice of a device used for oral delivery ofsolutes to the body of an animal are coated with a material that issoluble only at a basic pH, thus enabling the solute to be released inthe intestines of the animal rather than in the stomach.

[0094] Orifices or openings can be generated by methods well known tothose skilled in the art. For example, openings can be formed by, interalia, etched nuclear tracking; a laser, sonic or mechanical drilling; orelectrical discharge; etching; or by molding. The devices may beprepared by any method which provides the dispenser(s) and its housing,such as microfabrication, injection molding, etching from a solid blockin the shape of the housing, etc. The size of the device is governed bythe release characteristics, the total amount of solute(s) to bedelivered, and may range from microscopic devices, for example, to enterthe vascular circulation of animals, to very large devices, such as maybe placed in a water treatment tank, swimming pool or reservoir, forsustained release of algicide, etc.

[0095] In one embodiment, the device has one dispenser and one releaseorifice. In another embodiment, the device has more than one dispenser,each separated by impervious material and for which the release orificesare placed far enough apart so as to not interfere with each other. Inone embodiment, the one or more dispensers contain one or more solutematerials. In another embodiment, a device with more than one dispenser,each separated by impervious material, has one release orifice for eachdispenser housing.

[0096] In some cases, a hemispherical, conical, cubic or other shapeddispenser designed in accordance with the foregoing teaching may not besuitable for the finished device, and it will be desirous to surround orprovide the dispenser with an alternate finished shape. Suchconsiderations may be done, for example, to enhance consumer acceptanceof the device, or to eliminate edges or protruding parts to easeswallowing or insertion and, if necessary, retrieval, from a bodycavity. Such shapes may include, but are not limited to, a cone,cylinder, sphere, ellipse, hemisphere, capsule, rod, needle, or sheet.The foregoing non-limiting list is the shape of the finished device. Insome instances, the dispenser of the device and the housing may be onecontinuous material, wherein, for example, an inner hemispherical-shapedsolute reservoir element and associated gradient-forming element arebuilt up of, or hollowed out from, the same impervious material to forma finished housing of a different and more user-friendly shape. Theorifice(s) of the dispenser(s) may be fabricated to open to the surfaceof the housing to provide the exit from the device directly into thecompartment in which the device is placed; alternatively, thedispenser(s) may release into the interior of the housing and thereleased solute pass into the exterior compartment through one or moreoutlets. The housing may have numerous outlets, such as a porous orregularly perforated material, from which the solute is rapidly movedinto the exterior compartment. The device may be provided such thatbefore use, it may be opened for placing within the dispenser, thesolute, which may be for example in the form of a pre-manufacturedprescription drug tablet with no provision for controlled releasekinetics. These and other details of the particular features of thedevices are embraced within the teachings herein, and one of skill inthe art will readily design an outer casing or housing to house the oneor more dispensers to provide a compatible product to meet the needs ofthe particular application.

[0097] For example, an elliptical or capsule-shaped housing may beprovided to aid in the swallowing of a device that will release soluteduring transit through the digestive tract. The gradient-formingelement(s) of the dispenser(s) may empty to the exterior from outletsflush to the surface of the housing. A smooth-sided device without edgesis particularly desirable for other in-vivo uses as mentioned above,particularly for introduction into any body cavity or orifice, or forsurgical implantation and, if necessary, later retrieval. In anotherembodiment, an air freshener for using in a moving vehicle whichreleases from a volatile liquid at a constant rate is provided in theshape of a ornamental canister which can be affixed to the dashboard orhung from the rear-view mirror. The solute, in this case a liquid, iskept from agitation by the solute reservoir element housing being filledwith sponges or microporous beads in which the fragrant liquid issaturated. The finished shapes of the housings of such devices mayintegrate into the particular location of use, or incorporate estheticor other design features for acceptability of the end user.

[0098] Those of skill in the art will recognize in the design for adevice with more than one dispenser, that not all of the dispensersnecessarily need to have the same release parameters or shape. A devicemay have a dispenser with one particular shaped and sizedgradient-forming element, and another with another set of parameters,for example, a device comprising a form of chlorine for disinfecting aswimming pool may have one dispenser with no gradient-forming element,the dispenser containing the amount of chlorine necessary to “shock” thepool, for example, after a period of non-use or first use of the season.The shock provides a large amount of chlorine that would be undesirablefor human enjoyment. After the initial burst, the chlorine dissipatesafter a few days. A second dispenser in the device comprises agradient-forming element to provide zero-order release of chlorine of anamount compatible with swimming but to maintain antisepsis, for anextended period such as one month. Thus, the dispenser of the presentinvention may be combined with other devices to achieve desirablefeatures for the intended purposes of controlled release.

[0099] Devices of the present invention can be made in any size,including but not limited to devices on the order of a millimeter orless that can be put into a capsule and swallowed to those that are onthe order of tens of centimeters or larger, depending on the intendeduse.

[0100] In one embodiment, many devices, each carrying an amount ofsolute, are placed inside a capsule to be swallowed, such that, when thecapsule breaks open or the coating dissolves, the devices are releasedinto the body of the animal and solute is delivered from each device.Devices of the invention can be made from any material. In anotherembodiment, the devices are biodegradable. In yet another embodiment,the devices are made from non-biodegradable material.

[0101] A desired duration of release may be provided by configuring thedevice as described herein. In one embodiment, the methods of theinvention can be used to deliver solutes in a linear fashion over a timeperiod of from about 1 hour to about 1 month, more preferably for aduration of from about 5 hours to about 2 weeks, most preferably for aduration of from about 12 hours to about 48 hours. In a particularlypreferred embodiment, the methods of the invention are used to deliversolutes in a linear fashion to the body of an animal over a time periodof from about 8 hours to about 24 hours.

[0102] One or more solute can be delivered using the devices of thepresent invention. In one embodiment, the one or more solutes deliveredby the devices of the present invention are beneficial agents, such astherapeutic or prophylactic agents, that are delivered to the body of ananimal. These beneficial agents include, but are not limited to,antihypertensive agents such as diuretics, sympatholytic drugs,vasodilators and calcium channel blockers, analgesics such as opioidsand non-steroidal anti-inflammatory agents, antihistamines,antidepressants, hypnotics, sedatives, antiepileptic agents,antiarrhythmic agents, antiparasitic agents, antimicrobial agents,anti-Parkinson agents, antineoplastic agents, contraceptives,hypoglycemics, electrolytes, vitamins, minerals, nutriceuticals, localanesthetics, diagnostic agents, peptide growth factors, hormones andcytokines, stimulants such as amphetamine and methylphenidate,antianxiety agents such as benzodiazepines, and hematopoietic agentssuch as erythropoietin, stem cell factor, interleukins, and mixturesthereof. Such agents may also be diagnostic agents, such as radioimagingagents or substances for evaluating metabolism or clearance, e.g.,hepatic or renal function. In a preferred embodiment, the beneficialagent is erythropoietin. In another preferred embodiment, the beneficialagent is chloroquine, glipizide, calcium salts or parathyroid hormone.In one embodiment, a single beneficial agent is administered using thedevices of the invention. In another embodiment, combinations of two ormore beneficial agents are administered using the devices of theinvention. For example, a decongestant and an antihistamine can beco-delivered to the body of an animal for treatment of cold symptomsusing the devices of the invention. As noted above, a single device ofthe invention may comprise a plurality of release units, each of whichmay house a different solute and release it with particular desirablekinetics, such that the co-delivery of solutes may be optimized for eachindividual solute. Alternatively, one dispenser may comprise a pluralityof solutes which are co-dispensed with the same kinetics.

[0103] In one embodiment, the one (or more) solute is dissolved in asolvent. Those skilled in the art will appreciate that the type ofsolvent used to dissolve the one or more solutes depends on thesolubility properties of the one or more solutes. The solvent may be anaqueous solvent, an oil or non-aqueous medium. In one embodiment, theone or more solutes is a beneficial agent to be administered to the bodyof an animal and can be administered alone or together with apharmaceutically acceptable vehicle. In a specific embodiment, the term“pharmaceutically acceptable” means approved by a regulatory agency ofthe federal or a state government or listed in the U.S. Pharmacopeia orother generally recognized pharmacopeia for use in mammals. The term“vehicle” refers to a diluent, adjuvant, excipient, or carrier withwhich the one or more solutes is administered. Such pharmaceuticalvehicles are preferably liquids, such as water and oils, including thoseof petroleum, animal, vegetable or synthetic origin, such as peanut oil,soybean oil, mineral oil, sesame oil and the like. When administered toa mammal, the one or more solutes and pharmaceutically acceptablevehicles are preferably sterile. Saline solutions and aqueous dextroseand glycerol solutions can also be employed as liquid vehicles. The oneor more solutes, if desired, can also be administered with requiredamounts of wetting or emulsifying agents, or pH buffering agents.

[0104] Such agents in the device other than the agent desired to bedelivered are generally referred to herein as solute-modifying agents.Further to the above, other excipients may be used to modify the one ormore solutes or the properties of the device, such as but not limited tothe following activities. Agents to reduce the immunodetection of thesolute(s) in the device or to prevent colonization and clogging bymobile cells of the animal or environment in which it is implanted orplaced, such as white blood cells or fouling bacteria or othermicroorganisms; agents to chelate calcium to prevent clotting of plasmaor blood within the device; polymers to increase the viscosity of thesolute within the primary dispenser housing of the device; surfactantsto maintain solubility; etc. Such agents may or may not be released fromthe device along with the desired solute(s); upon release, such agentsmay dissociate from the solute(s) or be diluted such that they have noor minimal effect on the goal of the device and the methods for deliveryof solute.

[0105] In another embodiment, the one or more solutes to be deliveredusing the devices of the invention are not dissolved in a solvent, butare present in the device in dry form. In this embodiment, the one ormore solutes are dissolved or suspended in fluid when the device isimmersed, e.g., in the gastrointestinal fluids of an animal if thedevice is swallowed, or in water if the device is used to deliveralgicides to a swimming pool. The one or more solutes can be present inthe device as, inter alia, a powder, a crystal, an amorphous solid, andthe like.

[0106] In another embodiment, a user-fillable or refillable device maybe prepared with the features described hereinabove, such that, forexample, a prepared dosage form of a pharmaceutical agent, such as achloroquine tablet, may be loaded into a device by the user, swallowed,and prolonged linear delivery of the pharmaceutical agent achieved inthe body. An implanted device could be refilled at intervals, forexample, by transcutaneous injection into the device. Such devices maybe biodegradable. Another such device to release perfume at zero-ordermay be filled by the user and then carried on the person, for example,in the form of jewelry or secreted in the clothing, to provide apleasant, continuous level of local fragrance.

[0107] The present invention also includes methods for deliveringsolutes in a linear fashion using the devices of the invention. In apreferred embodiment, the methods of the invention are used to deliverone or more solutes to the body of an animal. In one embodiment, themethods of the invention are used to deliver one or more solutes thatare poorly soluble in aqueous media to the body of an animal. In thisembodiment, the one or more solutes in the device are dissolved in anoil or other non-aqueous medium. Without being bound by any theory, theapplicants observe that the rate of diffusion of a non-water-solublesolute from a device of the invention is partly dependent on thepartition coefficient of the solute in water. In another embodiment, theone or more solutes in the device are in dry form, and are dissolved orsuspended in liquid only when the device is immersed. The methods of thepresent invention can be used to deliver substances to the body of ananimal by various routes including, but not limited to, orally,sub-lingually, rectally, vaginally, sub-dermally, topically,intramuscularly, ocularly, nasally, aurically, intraperitoneally andintravenously. In one embodiment, the methods of the present inventionemploy an injectable device of the invention made from biodegradablematerial. In another embodiment, the device could be incorporated into adermal patch to deliver agents transdermally.

[0108] The devices of the invention may deliver other solutes, includingbut not limited to fragrances, deodorizers and other airborne volatilessuch as contained in air fresheners; industrial chemicals, such as maybe delivered at a sustained rate to an industrial process; disinfectantssuch as chlorine or bromine for delivery into swimming pools and hottubs; delivery of mosquito larvicide to ponds; delivery of fertilizer toplants. A device of the invention may be placed in a conduit or streamthrough which a fluid passes, the device delivering solute into themoving stream. These examples are merely illustrative and non-limitingwith regard to the wide variety of uses to which the instant devices andmethod may be put.

[0109] The present invention further includes kits for the delivery ofone or more solutes. Kits of the invention comprise one or more devicesof the invention. Kits of the invention can be used to deliver one ormore solutes to the body of an animal, to water tanks, swimming pools,hot tubs, plants, toilets, septic tanks, textiles, water towers,aquaria, ponds, and for industrial manufacturing processes. The devicesof the invention may be provided in reuseable form, such as a devicewhich may be opened for refilling. The device of the kit may be providedin an empty form without any solute, for filling by the user beforeplacement into the intended environment.

[0110] Manufacturing processes can be straighforwardly accomplishedusing methods well-known to one knowledgeable in the art ofpharmaceutics.

[0111] In a further embodiment of the invention, devices with dispensersillustrated in FIGS. 10-12 are provided. In the example of FIG. 10, aplurality of release orifices are provided around the base of a tubulargradient-forming element. In FIGS. 11-13, a plurality of source elementsare provided to a gradient-forming element which is provided in the formof a tubular indentation into the solute reservoir element, the sourceelements provided in circumferential bands in the gradient-formingelement, with increasing inter-band distance as the bands approach therelease orifice, which is flush with the surface of the solute reservoirelement. Both of these devices provide, in accordance with the presentinvention, the source elements and gradient-modifying elements toprovide desirable release characteristics as described herein.

[0112] The present invention may be better understood by reference tothe following non-limiting Examples, which are provided as exemplary ofthe invention. The following examples are presented in order to morefully illustrate the preferred embodiments of the invention. They shouldin no way be construed, however, as limiting the broad scope of theinvention.

EXAMPLE 1

[0113] A hemispherical brass mold was filled with chloroquine powder(approximately 500 mg) and was then compressed using a hydraulic press(6 ton) for 1 minute using either a flat or concave frustoconical pistonto obtain tablets with the following dimensions: piston: flatfrustoconical R_(sr) 0.635 cm 0.635 cm R_(se)  0.15 cm  0.15 cm R_(ro) 0.15 cm 0.075 cm θ 0° 45° B  0.25 cm  0.25 cm C₀   900 mg/mL   900mg/mL

[0114] The time dependent efflux of chloroquine was determined using theascending-column method (Langenbucher, 1969; J. Pharm. Sci. 59: 1265).The release rates of these two devices (as percent chloroquine load) isshown in FIGS. 3 and 4. Here, the hemisphere and frustoconicalhemisphere have similar total release (area under the curve; AUC) butthat with the frustoconical release modulator (FIG. 4), the peak releaseis about 50% of the hemisphere alone, but is maintained for a prolongedperiod of time.

[0115] The release kinetics of the frustoconical device can be changedin a number of ways by specifying different parameters, as will beevident to one skilled in the art. For example, by doubling the size ofthe exit orifice, from a radius of 0.075 cm to 0.150 cm, a higher,sustained peak release is obtained (FIG. 5), but at the expense of ashorter delivery duration.

EXAMPLE 2

[0116] Comparison was made between the release kinetics of chloroquineusing a device of the present invention and an immediate releasepreparation, ARALEN. Crystalline chloroquine was placed in two devices,designed to either deliver or not deliver a loading dose of drug. Thefilled devices were placed in a chamber through which water was pumpedat a rate of 0.75 ml/min. Perfusate was continuously collected at15-minute intervals by a fraction collector. The chloroquine content ofthe fractions was determined by light absorption with reference to astandard curve. The closed triangles define the release rate of thedevice delivering a loading dose, while the open circles define therelease rate of the device with a blunted loading dose (FIG. 6). Bothdevices reached a steady-state release of approximately 250 microgram/15minutes. The results demonstrate the ability of the devices as describedherein to release chloroquine in a controlled manner. Compared to themarketed preparation's exponential decrease of the release rate overtime, device 1 exhibits a linear decline of the release rate and device2 approximates a zero order release rate.

[0117]FIG. 7 shows the pharmacokinetic behavior in a human male subjectof the commercially-available chloroquine formulation ARALEN and aprototype device of the present invention, both preparations containing300 mg of base chloroquine. The data are consistent with the releasedynamics of the two preparations (see FIG. 6). The device of the presentintention achieved serum levels within a narrow range over a 24 hourperiod, when compared to ARALEN.

[0118]FIG. 8 shows data for the cumulative release of the macromoleculealbumin from a controlled-release device of the present invention. Thedata reflect zero order rate release of albumin over a duration of 24hours. Bovine serum albumin (MW 68,000) was dissolved in phosphatebuffered saline and loaded into a device designed to deliver a loadingdose. After an initial burst release, the rate becomes constant. Dataare plotted as the cumulated delivery of albumin over time, measured asdescribed for FIG. 5. Approximately 10 mg was delivered in 24 hours.

[0119]FIG. 9 shows the results of an in-vivo experiment, comparing thebiological response over a three weeks period of a single dose theprotein erythropoietin administered subcutaneously, to the parenteraldelivery of an identical dose of erythropoietin with acontrolled-release device of the present invention. The sustainedrelease of the protein was associated with greater biological activityat week 3, when compared to the subcutaneous administration.

EXAMPLE 3

[0120] Delivery of a Water-Insoluble Solute to Specific Sites

[0121] In one embodiment of the dispenser device, other solute orsolutes can be added to the solute reservoir element to make possible orimprove solubility of the target solute. The features of the dispenserthat make it suitable for prolonged, linear release of solute into theenvironment also apply to the interior of the dispenser. That is,solutes within the reservoir are retained, compared to conventionalformulations for which the solubilizing agent will rapidly diffuse away.

[0122] An example of the utility of the dispenser unit exists for theoral delivery of calcium salt(s) for the treatment of a variety ofconditions, e.g., osteoporosis. The most widely employed calcium salt iscalcium carbonate (containing 40% elemental calcium), which, however, isinsoluble in aqueous medium unless the pH is less than about 5.Therefore, standard oral preparations of calcium carbonate depend uponacidification in the stomach for dissolution. For individuals lackingthe ability to acidify stomach contents (e.g., those with perniciousanemia) cannot obtain calcium from these medications. Although normalindividuals may be able to solubilize calcium carbonate in the stomach,practically no absorption takes place there (<2% of the total). Instead,absorption occurs mainly by a specific, saturable mechanism in theremaining length of gut, with decreasing rank of absorption ileum (60%of total), jejunum (20%), and colon. Thus, for a bolus of calciumsolubilized in the stomach to be absorbed, calcium must remainuncomplexed with other moieties in the gut and be presented to a sectionof gut transporting below the maximum (saturated) rate.

[0123] To solubilize calcium and present it to sequential portions ofthe gut in a manner that minimizes the change of chelation or otherinactivating reactions, a hybrid dispenser with a frustoconicalgradient-forming element, and containing two solutes, is manufactured.Specifically, addition of ascorbic acid (or any other soluble acidifier)to a calcium carbonate load will, upon hydration, produce an low pHwithin the dispenser such that calcium carbonate goes into solution.During passage through the gut, continuous linear delivery of calciumwill be provided from within the protected environment of the dispenserlocally to each region of the gut capable of specific and non-specificabsorption of calcium.

[0124] By way of another example, the calcium compound contained in thedispenser could be tribasic calcium phosphate, which has approximatelythe same content of elemental calcium as does calcium carbonate. Bymixing powdered calcium phosphate and citric acid together in the molarproportions of 1:2 a mixture is produced which can be compressed into ahemispherical tablet under pressure. After applying a coatingimpermeable to water and providing a fenestration and gradient-formingelement, calcium ions will be released without the production ofeffervescence, as does calcium carbonate.

[0125] Using the methods developed here, it will be immediately obviousto one practiced in the art how to design and manufacture variouscalcium dispensers. As a specific, but not limiting example, powderedcalcium carbonate and ascorbic acid are mixed together in a 1:1milliequivalent ratio, compressed in a hydraulic press into a hemisphereof radius 5 rm and subsequently covered with a mixture of celluloseacetate/PEG 600/acetone, with a 3 mm diameter source element, and afrustoconical gradient-forming element with a height of 1 mm and arelease orifice of 1.5 mm.

EXAMPLE 4 Alternate Configurations of the Devices of the Invention

[0126] While the device depicted in three-dimensional form in FIG. 13represents a preferred embodiment of the present invention, with ahemispherical solute reservoir element, a single opening forming asource element (not seen in this depiction) and a frustoconicalgradient-forming element with a release orifice, many other alternateforms of the device are embraced by the teachings herein. Such examplesare shown in FIGS. 10-12 and 14. In FIG. 10, the dispenser comprises thesolute reservoir element, the source element (not visible in figure),and a gradient-forming element, but in this case, solute release isprovided from a plurality of release orfices situated in acircumferential pattern along the portion of a tubular-shapedgradient-forming element proximal to the solute reservoir element. Thedevice provides near zero-order rate release without an initial burst.

[0127] In FIG. 11, a cube-shaped solute reservoir element is provided,with a gradient-forming element taking the form of a tubular cavity fromthe surface and formed part-way through the cube. The release orifice ofthe gradient-forming element is present at the surface of the cube wherethe cavity begins. The source element is provide by a plurality ofcircumferentially-oriented rings of orifices spaced closely togethernear the bottom of the cavity and the space between the rings oforifices widening as they approach the surface of the cube. In analternate embodiment of the plural source element configuration, FIG. 12represents a tubular solute reservoir element with three bore holespassing almost but not completely through the solute reservoir. Thesource elements comprise a series of circumferentially-oriented orificesas in FIG. 11, thus the three interfaces of the bore-holes with thesolute reservoir element provide the release orifices of the device. Ina further embodiment particularly suitable and useful for parenterallocation and administration, FIG. 14 shows a tubular-shaped solutereservoir element with a longitudinal sector removed, the absent sectorproviding the gradient-forming element. The source element is providedby rows of orifices along the flat internal surfaces of the solutereservoir, the rows closely spaced towards the center and becoming moredistantly spaced towards the exterior.

[0128] In another embodiment of the invention, a dispenser may have asolute reservoir element in the shape of a truncated spherical cone anda gradient-forming element in the shape of a cylinder, as shown in FIG.16.

[0129] As mentioned above, the final shape of the device of theinvention may be tailored to the particular utility. For ease inswallowing, a dispenser may be provided in the shape of a capsule, suchas shown in FIG. 17. The capsule comprises a dispenser with ahemispherical solute reservoir element and a cylindricalgradient-forming element. FIG. 18 shows a similar easy-to-swallowcapsule containing four such dispensers, which in this case havedifferent shapes and thus release characteristics: two have a shortgradient-forming element and two have long such elements. All of thedispensers in a device may be the same, or some may be different,depending on the desired release parameters of the finished device. Allof the aforementioned alternate embodiments of a device of the inventionare merely illustrative of the variations in configuration of thecombination of a solute reservoir element, one or more source elements,and one or more gradient-forming elements, each of the latter with oneor more release orifices, to deliver one or more solvents withzero-order or near-zero-order rate release over time, without an initialrelease.

[0130] As mentioned above, the device of the invention may be adapted tohold one or more of the aforedescribed dispensers. For a device with aplurality of such exterior openings, each orifice associated with arelease orifice of a dispenser, each exterior opening is at least threerelease-orifice-radii apart from another, preferably ten radii apart.FIG. 27 depicts the release kinetics from chloroquine-containing deviceshaving up to 12 dispensers in a group, with decreasing distance amongthe release orifices with increasing numbers of dispensers. Eachdispenser has a 1 mm high gradient-forming element, a 3 mm diameterrelease orifice and a total length of dispenser of 3 cm.

EXAMPLE 5

[0131]FIG. 19 shows the theoretical modulation of initial release ratesand time to reach steady state caused by cylindrical gradient-formingelements of different dimensions attached to identical truncatedspherical cones as determined by numerical solution of the diffusionequation. A common truncated cone, one which was squat (i.e. ratio ofbase to tip greater than 1), and a fixed length of the gradient-formingelement was used for each of the conditions plotted. The followingparameters were evaluated: (1) a device without a gradient-formingelement (“no gradient-forming element”); (2) a device with agradient-forming element having a radius 1/3 that of the cone pore (1:3gradient-forming element); (3) a device with a gradient-forming elementof radius 1/7 the pore radius (1:7 gradient-forming element); and (4) adevice having a gradient-forming element radius 1/15 that of the poreradius (1:15 gradient-forming element). The device without agradient-forming element exhibits an initial rapid decay to aquasi-constant efflux rate for times >>200 arbitrary units. Addition ofa gradient-forming element with a 1:3 ratio blunts the initial rapiddecay but also increases the flux as well as its constancy. By selectionof a 1:7 gradient-forming element relationship, not only can the initialrapid release phase be completely blunted, but in addition the effluxrate is now truly zero order. Decreasing the gradient-forming elementradius further (e.g., 1:15) serves only to decrease further the rate offlux, which remains essentially constant. The exact relationshipsbetween these parameters, including the influence of thegradient-forming element height, are explored in an example below.

[0132]FIG. 20 illustrates the actual release of chloroquine fromfrustoconical devices constructed according to the theoreticalcalculations generated for FIG. 19. As experimentally verified for a 1:3ratio, a gradient-forming element will not only blunt the initial burstof release, but will also increase the delivery duration compared to adispenser lacking a gradient-forming element.

[0133]FIG. 21 illustrates that a frustoconical device with a cylindricalgradient-forming element can be designed to deliver chloroquine in azero-order manner at varying rates, in contrast to an identical butuncoated cone which delivers with an initial burst, followed by a rapidexponential decay, or a cone without a gradient-forming element. FIG. 22shows the relative flux from frustoconical dispensers with cylindricalgradient-forming elements of 1 mm and 3 mm, compared to an uncoateddispenser and a coated dispenser without a gradient-forming element.

EXAMPLE 6 Exemplary Devices to Deliver Drugs Orally

[0134] Design of a device to deliver solutes orally is typicallyconstrained by the requirement for a nearly complete release of solutewithin the normal transit time in the gastrointestinal tract ofpatients; i.e., approximately 24 hrs. FIGS. 23 and 24 illustrate twodifferent forms of a device to deliver chloroquine orally by constantrelease with a common feature of an identical base diameter. FIG. 24corresponds to a moderately slender cone of vertex angle 25° (“thickdevice”) whereas FIG. 23 corresponds to a wider cone of vertex angle 60°(“thin device”). Both assume a cylindrical gradient-forming elementheight of 0.01 cm. Using the flux equation given for frustoconicaldispensers above for a load concentration of chloroquine at 500 mg/mL,and a diffusion coefficient of 5×10⁻⁶, the parameters (shown in thetable below) are selected to provide a release of 1.2 mg/hr for thethick device. The total load of chloroquine is ˜49 mg, with ˜29 mg beingdelivered over 24 hrs. In contrast, the thin device provides a smallerflux of ˜670 microgram/hr, but releases ˜16 mg of the load of ˜16.5 mg.By modifying parameters in the flux equation, a practitioner of the artwill be able to design straightforwardly a device to provide a specifiedprofile of solute release. THIN AND THICK DEVICE CHARACTERISTICS VERTEXANGLE THIN DEVICE THICK DEVICE (2θ) (120°) (50°) HEIGHT (H) 0.22 cm0.815 cm FRUSTUM (B) 0.2 cm 0.33 cm TIP (T) 0.02 cm 0.487 cm VOLUME 33μL 97 μl BASE RADIUS (R2) 0.38 cm 0.38 cm RELEASE ORIFICE RADIUS 0.034cm 0.226 cm (R1) GRADIENT-FORMING 0.03 cm 0.06 cm ELEMENT RADIUS (Rc)GRADIENT-FORMING 0.1 mm 0.1 mm ELEMENT LENGTH (Z) [CHLOROQUINE] 500,000μg/mL 500,000 μg/mL

[0135] Exemplary Device to Deliver Drugs Parenterally.

[0136] Requirements for parenteral delivery of drugs include a shape forease of insertion and generally a prolonged delivery duration comparedto oral administration. These factors generally require a long, slenderdevice profile. As an example, FIG. 27 illustrates one such deviceconstructed to deliver the protein erythropoietin (MW ˜34,000) at a rateof 20 units per day for a 30 day period. The parameters selected aretabulated below. PARENTERAL DEVICE CHARACTERISTICS VERTEX ANGLE (2θ) 10°HEIGHT (H) 0.435 cm FRUSTUM (B)  0.35 cm TIP (T) 0.085 cm VOLUME  0.82μL BASE RADIUS (R2) 0.038 cm (21.5 gauge) RELEASE ORIFICE RADIUS (R1)0.015 cm GRADIENT-FORMING ELEMENT 0.004 cm RADIUS (Rc) GRADIENT-FORMINGELEMENT  0.2 cm LENGTH (Z) [rhEPO] 10⁶ U/mL (10 mg/mL) Units/device ˜650output 0.9 U/hr; ˜20 U/day Delivery duration ˜30 days

[0137] Many variations in construction will be apparent to those skilledin the art. For example, a high concentration of solute can be placed asa depot in the base of a dispenser which will provide a constantconcentration over a long period of time.

EXAMPLE 7 Manufacture and Validation of a Truncated Cone with aCylindrical Gradient-Forming Element for the Oral Delivery ofChloroquine

[0138] Manufacturing of devices with a solute reservoir element havingthe shape of a truncated right circular cone and a gradient-formingelement having the shape of a cylinder can be accomplished in many wayswhich will be evident to those skilled in the art. Processes caninclude, among others, molding, casting, extruding, or compression ofsolute with or without an excipient into the required geometrical shapeand dimensions. Alternatively, powdered solute or solutes can be placedinside the shell of a dispenser with the solvent subsequently derivedafter administration from the external environment entering the cavityto initiate the process of diffusion. Wicking, such as the incorporationof fibers, wetting agents, or a hydrophilic matrix, etc. can beincorporated with the solute mixture within the device cavity andgradient-forming element to aid in filling the cavity with solvent.Further, other substances with specific purposes other than solutedelivery can also be incorporated. For example, immunomodulatingsubstances may be added to reduce local inflammatory response forimplanted devices or buffering salts added to maintain the internal pHof the dispenser within a specific range.

[0139] Furthermore, the manufacture of a device having a solutereservoir element having the shape of a hemisphere and agradient-forming element having the shape of a right truncated cone canbe accomplished in many ways which will be evident to those skilled inthe art. Processes can include, among others, molding, casting,extruding, or compression of solute with or without an excipient intothe required geometrical shape and dimensions. In the example of anintermediate form during manufacture shown in FIG. 26, a symmetricdumbbell-shaped cast comprising two devices connected from releaseorifice to release orifice is prepared, and is then coated withimpervious material. Cutting apart at the midpoint produces twoidentical dispensers. In an alternate embodiment, the dumbbell may beasymmetric to produce two types of dispensers with differentcharacteristics.

REFERENCES CITED

[0140] All references cited herein are incorporated herein by referencein their entirety and for all purposes to the same extent as if eachindividual publication or patent or patent application was specificallyand individually indicated to be incorporated by reference in itsentirety for all purposes.

[0141] Many modifications and variations of this invention can be madewithout departing from its spirit and scope, as will be apparent tothose skilled in the art. The specific embodiments described herein areoffered by way of example only, and the invention is to be limited onlyby the terms of the appended claims, along with the full scope ofequivalents to which such claims are entitled.

What is claimed is:
 1. A device for the continuous, linear, sustainedrelease of one or more solutes comprising at least one dispenser, saiddispenser comprising i) a solute reservoir element, said solutereservoir element defined by a fluid-impervious and solute-imperviouswall and comprising a shape of a hemisphere, said hemisphere having aflat face, a center of said flat face, and a radius; ii) a sourceelement in said wall, said source element consisting of a circularpassageway at said center of said flat face of said hemisphere, saidsource element having a radius, said passageway allowing the diffusionof a solute from said solute reservoir element into a gradient-formingelement; iii) a gradient-forming element in fluid registry with saidsource element and into which said solute diffuses from said solutereservoir element, said gradient-forming element having afluid-impervious and solute impervious wall and a shape of a truncatedright circular cone with a base, a vertex, and a height from said baseto said vertex; iv) a release orifice defined by said vertex of saidgradient-forming element for the diffusion of said solute from saiddispenser, said release orifice having a radius; wherein a ratio of saidradius of said hemisphere to said radius of said source element is equalto or greater than about two, and said height of said gradient-formingelement is equal to or less than about four times a ratio of said radiusof said source element squared to said radius of said release orifice.2. The device of claim 1 wherein said frustum of a cone has a vertexangle of between about 10° and about 135°.
 3. The device of claim 2,wherein said vertex angle is about 60° to about 120°.
 4. The device ofclaim 1, wherein said solute reservoir element is empty.
 5. The deviceof claim 1, wherein said solute reservoir element contains a poroussubstrate.
 6. The device of claim 1, wherein said dispenser has a shapeselected from the group consisting of cone, cylinder, sphere, ellipse,hemisphere, capsule, rod, needle, and sheet.
 7. The device of claim 1,wherein said solute reservoir element contains a solute at an initialconcentration C_(o), said radius of said solute reservoir element isR_(sr), said source element with radius R_(se), said solute having adiffusion coefficient D, said vertex angle of said gradient-formingelement is 2θ, said solute has a release rate from said release orifice,said release orifice has a radius R_(ro), said release rate is given by:wherein i is said rate of solute flux from said release orifice atsteady state.
 8. The device of claim 1, wherein said release orifice iscoated with a material that is soluble under preselected conditions. 9.The device of claim 8, wherein said material is soluble at a preselectedpH.
 10. The device of claim 1, wherein said one or more solutes is atherapeutic agent.
 11. The device of claim 10 wherein said therapeuticagent is selected from the group consisting of a calcium salt,parathyroid hormone, antihypertensive agents, diuretics, sympatholyticdrugs, vasodilators, calcium channel blockers, analgesics, opioids,non-steroidal anti-inflammatory agents, antihistamines, antidepressants,hypnotics, sedatives, antiepileptic agents, antiarrhythmic agents,antiparasitic agents, antimicrobial agents, chloroquine, anti-Parkinsonagents, antineoplastic agents, contraceptives, hypoglycemics,electrolytes, vitamins, minerals, nutriceuticals, local anesthetics,diagnostic agents, peptide growth factors, hormones, cytokines,stimulants, amphetamine, metbylphenidate, antianxiety-agents,benzodiazepines, hematopoietic agents, erythropoietin, stem cell factor,interleukins, and mixtures thereof.
 12. The device of claim 1, whereinsaid one or more solutes is an erythropoietin.
 13. The device of claim1, wherein said one or more solutes is chloroquine.
 14. The device ofclaim 1, wherein said one or more solutes is dissolved in a solvent orpharmaceutically acceptable vehicle.
 15. The device of claim 1, whereinsaid one or more solutes is dry.
 16. The device of claim 1, wherein saidone or more solutes is not water soluble.
 17. The device of claim 1which contains a solute-modifying agent.
 18. The device of claim 1wherein said ratio of said radius of said hemisphere to said radius ofsaid source element equal to or greater than about
 5. 19. The device ofclaim 18 wherein said ratio is equal to or greater than about ten. 20.The device of claim 1 wherein said height of said gradient-formingelement is equal to or less than about two times a ratio of said radiusof said source element squared to said radius of said release orifice.